APPLICANT'S ABSTRACT: Preclinical research on endogenous opioid system involvement in alcohol reinforcement has led to studies of the effectiveness of the opioid antagonist naltrexone for treatment of alcohol dependence. In two clinical trials, naltrexone decreased alcohol craving and drinking in alcohol dependent subjects. Recently, naltrexone has been studied under more diverse conditions, including heterogeneous subject populations, longer medication periods, different dose levels and different therapy conditions. Results have been more variable than those of the original clinical trials and it is now clear that many alcohol dependent patients do not benefit from naltrexone as administered under current practice standards. These recent studies highlight the need for research to identify predictors of naltrexone treatment response. Our research has identified a negative relationship between serum 6-beta naltrexol level (naltrexone's major metabolite) and alcohol consumption in patients on 50 or 100 mg naltrexone. Above a level of 40 ng/ml 6-beta-naltrexol, alcohol consumption was fully suppressed; however, as reported in earlier studies on naltrexone metabolism, 6-beta-naltrexol levels were highly variable across patients. The proposed research will examine the effectiveness of several opioid-related variables as predictors of naltrexone treatment outcomes. First, we will measure endogenous opioid system activity by naloxone challenge test as a marker of opioid system dysfunction resulting from chronic drinking. Second, we will measure unblocked mu opioid receptor binding at the 24-hr nadir of steady-state naltrexone levels using Positron Emission Tomography (PET). Third, we will obtain daily serum 6-beta-naltrexol levels during naltrexone induction as a marker of individual differences in naltrexone bioavailability. Fourth, we will measure self-reported alcohol craving, withdrawal and mood. Alcohol-dependent subjects (N= 192) with no other substance abuse or psychiatric disorders will be randomized to: placebo, once daily naltrexone 100 mg, or twice daily naltrexone 50 mg. All subjects will undergo a 2-week inpatient protocol, including alcohol withdrawal, naloxone challenge test, naltrexone induction according to dose condition, and PET imaging. After discharge, subjects will participate in a 12-week outpatient clinical trial with regular measurement of drinking, craving and mood, and 6-beta-naltrexol. Follow-up will be conducted 6 and 12 months post-enrollment. Results will provide new scientific and clinical knowledge on predictors of naltrexone treatment response and the interrelationships of endogenous opioid activity, mu opioid receptor blockade by naltrexone, serum 6-beta-naltrexol levels and alcohol craving and mood.